The non-cross-reactive antigens keyhole limpet hemocyanin (KLH) and polymerized human serum albumin (HSA) were injected into the hind foot pads of rabbits. Months later the draining lymph nodes were removed and cell cultures prepared containing various concentrations of KLH or native HSA. The cultures responded to some concentrations of KLH by synthesizing not only homologous IgG antibody but also heterologous IgG antibody to HSA. The cells responded to some doses of HSA with synthesis of antibody to KLH as well as to HSA. The cultures responded to other concentrations of KLH with an inhibited response to HSA. The non-specific enhancement of the antibody response appears to require thymus-dependent lymphocytes. Soluble factors produced by activation of lymphocytes with antigen can cause non-specific enhancement or inhibition of the antibody response. Other soluble factors produced by antigenic stimulation of lymphocytes evoke specific enhancement of the antibody response. The relationship of regulation of the antibody response as a result of cell-cell interactions to that of regulation by interactions of soluble factors and cells is being analyzed. The nature, activities and mode of action of the soluble regulatory substances are being determined.